Morbidity and mortality rates of many preventable conditions are disproportionately high in many American Indian (Al) populations. Well documented health disparities for Al adults and youth related to abuse of alcohol, tobacco, and illicit drugs extend to the growing urban Al population, who now constitute over 60% of the total Al population. Al youth report higher rates, earlier onset, more severe consequences, yet less perceived risk of harm of substance use compared to their non-native counterparts. To thwart the early onset and aftermath of substance abuse, primary prevention efforts have been undertaken with Al youth in several U.S. regions. But programs have not explicitly targeted urban Al youth using rigorous culturally grounded prevention methods. The proposed study draws upon the project team's research on the etiology of substance use among Al youth of the urban southwest to conduct translational research that recognizes salient risk and resiliency factors identified by these youth, social and relational contexts that expose them to substances, and their culturally appropriate drug resistance strategies. The first aim of the study is to create a culturally grounded substance abuse prevention intervention targeting urban Al youth in 7th and 8th grades through a modification of a SAMHSA Model universal prevention program, keepin it REAL. The adaptation will employ emerging principles for adapting programs for new target populations in ways that increase cultural fit while maintaining fidelity to core program components. The intervention will be adapted, piloted, evaluated, culturally validated, and revised accordingly. A second aim is to test the feasibility and efficacy of the adapted substance abuse prevention intervention in a randomized control trial (RCT). Ecodevelopmental Theory provides the framework for understanding key influences on Al youths' substance use. Participatory action research methods will be used to adapt the intervention, including focus groups with key Al informants (adults and youth), working in collaboration with the designers of the original intervention and in coordination with the area's largest provider of social services to urban Indians. The RCT will be conducted in existing groups for Al students enrolled in urban school districts. The resulting prevention intervention will address the needs of an under-served group severely affected by health disparities, and advance knowledge on effective translational research strategies for adapting prevention interventions for ethnically diverse youth.